The long-term goal of this project is the development of genetic approaches to treat neurodegenerative diseases. One of the strategies pursued is the discovery of small molecules or oligodeoxynucleotides that alter the expression of relevant endogenous genes within the brain. The genes investigated are those encoding two neurotrophic factors brain- derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) and the two dopamine receptor subtypes expressed in the striatum, D1A and D2. 1. We found that mRNA levels of both BDNF and GDNF genes are markedly enhanced in a glioma cell line by increased intracellular calcium levels. This observation provides an explanation for the well known dramatic increase in BDNF expression with ischemic insult, seizures and trauma all of which result in the release of glutamate and influx of CA2+. The five alternate promoters in the BDNF gene responded to different degrees to the calcium ionophore. 2. We had previously characterized the structure of the human D1A dopamine receptor gene. We now discovered that its transcriptional control is quite complex with regulatory sequences and DNA-protein binding sites along the approximately 900 bp long 5' untranslated region. We also found that POU family of transcription factors differentially activate this gene. 3. The D2 dopamine receptor is traditionally recognized to be the main mediator of the motor and endocrine effects of dopamine. We had previously found a strong negative modulatory sequence in this gene which binds to a 130 kDa protein and Sp1. During FY95, we cloned this unknown protein as well as four additional transcription factors all belonging to the zinc finger family of proteins. 4. The D3 dopamine receptor is expressed at low levels in the motor striatum which might be important for relaying dopaminergic messages to the output regions of the basal ganglia. We found that chronic dopaminergic blockade with several antipsychotic drugs increases D3 mRNA levels in olfactory tubercle and nucleus accumbens of rats but not in motor striatum. Thus, the extrapyramidal syndrome of chronic neuroleptic therapy is not due to D3 receptor upregulation in the striatum. Consequently, antagonists selective of the D3 subtype may be effective antipsychotics without the adverse motor effects.